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LBP-1a gene mutation linked to disruption of normal fetal development

09.08.2004


A defect in blood vessel formation in human placenta due to loss of LBP-1a gene is linked to spontaneous abortion, infant death and long-term neurological or cardiovascular problems



The lack of a gene called LBP-1a in the mouse embryo prevents normal growth of blood vessels in the placenta. This finding suggests that a similar defect in humans could play a role in fetal growth retardation, infant mortality and spontaneous abortion. These results, by investigators at St. Jude Children’s Research Hospital, are published in the August issue of Molecular and Cellular Biology (MCB). The finding could one day help scientists develop a test to identify women who have this mutation and are at risk for these problems, as well as guide development of new prevention treatments.

The researchers also report that the protein made by the LBP-1a gene is a member of a family of proteins called the "grainyhead transcription factors." This is the first gene-based evidence that a member of this family is essential for normal development of blood vessels outside the growing embryo. A transcription factor is a protein that activates a gene and in this way regulates a specific process.


The study found that mouse embryos lacking the LBP-1a gene were normal during the first 9 ½ days of development, a time during which they survive by exchanging gases, nutrients and toxic breakdown products of food with their outside environment, the amniotic fluid. But embryos lacking LBP-1a failed to produce the extensive network of blood vessels that extends into the part of the developing placenta called the labyrinthine layer and mingles with the sinuses containing blood from the mother. A sinus is a channel inside certain tissues that contains blood.

In the absence of this link to the mother’s blood in the placenta, embryos suffered growth retardation by day 10 ½ of pregnancy, and died the next day.

The finding strongly suggests that LBP-1a plays a critical role in the production of blood vessels outside the embryo that extend into the placenta, according to John M. Cunningham, M.D., an associate member of St. Jude Hematology/Oncology. Cunningham is senior author of the MCB report.

"This will likely help us explore the contribution of special proteins called growth factors in regulating the activity of LBP-1a and the development of blood vessels outside the embryo," Cunningham said.

The blood vessel defect caused by lack of LPB-1a is similar to complications in human pregnancy linked to pre-eclampsia and missed abortion. Pre-eclampsia is an abnormal condition during pregnancy that triggers hypertension and fluid retention in the mother and can lead to the more severe condition of eclampsia, which causes convulsions and coma. Missed abortion refers to a pregnancy in which the embryo stops developing normally, and which usually ends in spontaneous abortion.

"Lack of normal blood vessel formation in the yolk sac and placenta in humans could also cause intra-uterine growth retardation (IUGR)," said Vishwas Parekh, M.D., a postdoctoral fellow in the Cunningham lab and lead author of this work.

IUGR is linked to infant death and newborn defects in the nervous and cardiovascular systems, as well as to type 2 diabetes later in life. Type 2 diabetes is caused by the inability of the body’s cells to use insulin.

The St. Jude researchers found that mouse embryos lacking LPB-1a had no major abnormalities in their organ systems, overall body shapes or blood cell development.

"This strongly suggested that the growth retardation was not due to a problem in the embryo itself," Parekh said. Scientists found almost a complete lack of blood vessels in the yolk sacs connected to embryos lacking LPB-1a and pools of free fetal blood in the amniotic cavity--the space inside the membrane surrounding the embryo. The blood vessels that did form were abnormally large and thin; and no fetal blood vessels reached the maternal blood sinuses.

The St. Jude team also noted that a critical layer of cells that forms the placenta--the trophoblast cells--was normal in fetuses missing LPB-1a. This further supported the idea that it was the lack of normal blood vessels and not another abnormality in the placenta that caused fetal growth retardation.

The researchers concluded that normal formation of the placenta cannot occur in embryos lacking LBP-1a because of a defect in the formation of critical blood vessels needed to obtain nutrients from the mother’s blood while expelling waste products. Other authors of this paper are Amy McEwen, Virginia Barbour, Yutaka Takahashi and Jerold E. Rehg (St. Jude) and Stephen M. Jane (Royal Melbourne Hospital Research Foundation, Australia).

Bonnie Cameron | EurekAlert!
Further information:
http://www.stjude.org

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